Olive-derived oleocanthal as a novel natural product molecule to restore cerebrovascular function and integrity in a CAA mouse model Project Summary Cerebral vascular dysfunction plays a critical role in the pathology of cerebral amyloid angiopathy (CAA) and is often observed in Alzheimer?s disease (AD). Therapeutics that target the blood-brain barrier (BBB) may be beneficial in multiple neurodegenerative disorders including AD, CAA, and vascular dementia. Studies from our laboratory demonstrated oleocanthal, a natural phenolic compound isolated from extra-virgin olive oil, as a novel molecule with neuroprotective effects against CAA and AD in mouse models. In addition, new preliminary data obtained from our recently developed unique in vitro BBB model with CAA characteristics showed oleocanthal to rectify the compromised integrity and function of this CAA-BBB model. The overall goal of this project is to tie findings obtained from our pre-clinical in vivo studies and from the novel in vitro BBB model with cutting edge in vivo imaging tools focus on studying the BBB function and with behavioral studies to determine oleocanthal as a promising therapeutic for vascular A? pathogenesis disorders like CAA and AD. Our central hypothesis is that oleocanthal is a novel therapeutic molecule that targets the BBB for prevention and/or treatment of vascular A? pathogenesis. We will test this hypothesis by pursuing the following specific aims: Aim 1) Investigate the in vivo efficacy of orally administered oleocanthal to improve cerebral blood flow and BBB integrity, reduce synaptotoxicity, and improve learning and memory deficits in transgenic mouse model of CAA/AD. This Aim will be examined via the Sub-Aims: a) determine functional effects of oleocanthal treatment using a battery of cognitive tasks, b) investigate oleocanthal effect on cerebral blood flow and BBB permeability and functionality using the new state-of-the art system Multi-Spectral Optoacoustic Tomography (MSOT), and c) evaluate oleocanthal effect on vascular and cerebral A? load, synaptic integrity and neurogenesis. Aim 2) Determine the pharmacokinetics and brain distribution of orally administered oleocanthal in wild type mice. A multidisciplinary team of investigators with expertise in neurologic disorders, behavioral testing, molecular imaging and pre-clinical drug development for AD therapeutics are committed to the project. Outcomes of this work will support and advance therapeutic development of oleocanthal toward clinical trials.